US3872147A

US3872147A - 1-phenoxy-2-hydroxy-3-alkylamino-propanes

Info

Publication number: US3872147A
Application number: US204316A
Authority: US
Inventors: Herbert Koppe; Werner Kummer; Helmut Stahle; Karl Zeile; Albrecht Engelhardt
Original assignee: CH Boehringer Sohn AG and Co KG
Current assignee: CH Boehringer Sohn AG and Co KG; Boehringer Ingelheim GmbH
Priority date: 1967-12-13
Filing date: 1971-12-02
Publication date: 1975-03-18
Anticipated expiration: 1992-03-18
Also published as: NL151354B; YU33949B; AT294799B; SE367396B; IL31266A; AT292670B; ES361189A1; AT292673B; AT292680B; YU237874A; BG16329A3; ES375449A1; AT292677B; YU33948B; YU33946B; ES375451A1; AT298463B; FR1596100A; JPS5220457B1; FI49497B

Abstract

The compounds are 1-phenoxy-2-hydroxy-3-alkylamino-propanes and non-toxic acid addition salts thereof, useful as Beta adrenolytics and hypotensives in warm-blooded animals.

Description

United States Patent [1 1 Kiippe et al.

[73] Assignee: Boehringer lngelheim GmbH,

lngelheim am Rhein, Germany [22] Filed: Dec. 2, 1971 [21] Appl, No: 204,316

Related U.S. Application Data [63] Continuation of Scr. No, 781,985, Dec, 6, 1968,

abandoned.

[30] Foreign Application Priority Data Dee 13, 1967 Germany 1643625 1 Mar. 18, 1975 [52] U.S. Cl 260/465 E, 260/340.5, 260/465 D. 260/471 A, 260/479 S, 260/519, 260/559 A, 260/570.7, 260/562 A, 424/282. 424/304,

[51] Int. Cl. C07c 121/78 [58] Field of Search 260/465 E [56] References Cited UNITED STATES PATENTS 3,459,782 8/1969 Koppe et a1, 260/465 Primary E.raminerLewis Gotts Assistant E.\-aminerD01ph H. Torrence Attorney, Agent, or FirmHammond & Littell [57] ABSTRACT The compounds are l-phenoxy-2-hydroxy-3- alkylamino-propanes and non-toxic acid addition salts thereof, useful as B-adrenolytics and hypotensives in warmblooded animals.

3 Claims, No Drawings ---lt;t (I) wherein y R is alkyl of to 8 carbon atoms comprising at least one quaternary carbon atom which is attached, directly or through an alkylene chain of l to 4 carbon atoms, to the amino nitrogen atom, R, is cyano, carboxyl, hydroxyl, amino, nitro, trifluoromethyl, alkyl of 1 to 5 carbon atoms, alkenyl of 2 to 5 carbon atoms, alkinyl of2 to 5 carbon atoms, alkenyloxy of 2 to 5 carbon atoms, alkinyloxy of 2 to 5 carbon atoms, hydroxyalkyl of 1 to 5 carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms, alkylaminoalkyl of 2 to 5 carbon atoms, dialkylaminoalkyl of 3 to 5 carbon atoms, alkylamino of l to 5 carbon atoms, cyanoalkyl of2 to 5 carbon atoms, alkoxycarbonyl of 2 to 5 carbon atoms, alkylaminocarbonyl of 2 to 5 carbon atoms, alkylthio of l to 5 carbon atoms, acyl, aeyloxy, acylamino, (each of l to 5 carbon atoms) halogen or alkoxy of l to 5 carbon atoms in mor p-position with respect to the propanolamino side chain,

R is hydrogen, halogen, cyano, alkyl of 1 to 4 carbon l atoms, alltoxy of l to 4 carbon atoms or alkenyl of 2 to 4 carbon atoms,

R is hydrogen, halogen, alkyl of l to 4 carbon atoms or alkoxy of l to 4 carbon atoms, and

R and R together with each other, are 3,4-

methylenedioxy, with the proviso that R, is other than 2-bromo when R is 1,1-diethyl-butyl and R and R are hydrogen, and their non-toxic, pharmacologically acceptable acid addition salts.

The compounds ofthe formula 1 may be prepared by various methods involving well known chemical principles, among which the following have proved to be particularly efficient and convenient:

Method A By reacting a compound of the formula lit l or CH(OH)CH Hal, where Hal is halogen, with an alkylamine of the formula NH R lll. wherein R has the same meanings as in formula I, in a manner and under conditions which are customary for such reactions. Method B By splitting off an easily removable protective group from a compound of the formula i. (IV) wherein R, R R and R have the same meanings as in formula 1 and G is a hydrolytically removable protective group, such as acyl or acetal. Method C By converting the substituent A in a compound ofthe formula into a substituent R,, as defined in formula I. R, R and R in formula V have the same meanings as in formula 1, and A may have any one of the following meanings:

Aldehyde (-CHO), which is convertible into CH- 0H or CH;, by reduction;

-CONH or CH=NOH, which are convertible into cyano by dehydration;

Haloalkyl, which is convertible into aminoalkyl, al kylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl or alkoxyalkyl by reaction with ammonia, an amine, water or aliphatic alcohols;

Hydroxyl, which is convertible into alkoxy by etherification;

Nitro, which is convertible into amino by reduction;

Alkoxycarbonyl, which is convertible into carboxyl by'hydrolysis; or

Amino, which is convertible into cyano or halogen by diazotization and heating with copper(l)-cyanide or copper (l)-halide, respectively.

The conversion ofa compound of the formula V into a compound of the formula 1 is effected by applying the required known reaction, i.e. dehydration exchange reaction, condensation, alkylation, reduction or diazotization and subsequent heating with a coppertl)-salt, etc, to the particular compound of the formula V. Method D By introducing a halogen substituent into the phenyl ring of a compound of the formula wherein R has the same meanings as in formula 1, and Ar is Q go 2 wherein R R and R have the same meanings as in formula 1 and X is hydrogen or a cation, especially an alkali metal cation. An epoxide of the formula 11, in turn, may be used for the preparation of other starting compounds; for example, a halohydrin of the formula 11 may be prepared by reacting the corresponding epoxide with a hydrohalic acid.

A compound of the formula IV may be prepared by reacting a halohydrin of the formula 11 with a compound which forms a protective group G, such as vinyl ether or dihydropyran, and subsequently reacting the compound of the formula (VIII) formed thereby, wherein R R and R and G have the same meanings as in formula IV and Hal is halogen, with an amine of the formula Ill.

Finally, compounds of the formulas V and V1 may be prepared pursuant to method A described herein, i.e. starting from a corresponding phenol by way of the corresponding l-phenoxy-2,3-epoxypropane and reaction of the latter with an alkylamine of the formula III.

The compounds according to the present invention comprise an asymmetric carbon atom and therefore occur as racemic mixtures as well as in the form of optically active antipodes. The latter may be obtained by separating the racemic mixture with the aid of customary auxiliary acids, such as dibenzoyl-D-tartaric acid or D-3-bromocamphor-8-sulfonic acid, or also by using the corresponding optically active starting compound.

The compounds of the formula 1 are organic bases and therefore form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, maleic acid, acetic acid,

'4 oxalic acid, lactic acid, tartaric acid, 8- chlorotheophylline and the like. Such acid addition salts may be obtained by conventional methods, for instance, by dissolving the free base in a suitable inert solvent and acidifying the solution with the desired inorganic or organic acid.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

EXAMPLE 1 Preparation of l-(o-cyano-phenoxy)-2-hydroxy-3- [(a,a-dimethyln-propyl)-amino]-propane and its hydrochloride by Method A 14 gm of 82% a,a-dimethyl-n-propyl-amine were added to a solution of 10.5 gm (0.06 mol) of l-(ocyano-phenoxy)-2,3-epoxy-propane in cc of etha- "nol, the mixture was allowed to stand for 24 hours at 20C., and thereafter it was refluxed on a boiling water bath for about 3 hours. Subsequently, the ethanol was distilled off in vacuo, the residue was digested with dilute hydrochloric acid, the insoluble matter was separated, and the acid solution was made alkaline with sodium hydroxide. The base precipitated thereby was taken up in ether, the organic phase was dried over magnesium sulfate, and the ether was distilled off. The residue, 1-(o-cyano-phenoxy)-2-hydroxy-3-[(mm dimethyl-n-propyl)-amino|-propane, was dissolved in acetonitrile, the solution was acidified with ethereal hydrochloric acid, and the crystalline precipitate was rc crystallized from ethanol/ether, yielding 7.6 gm of the colorless crystalline hydrochloride, m.p. l34l36C., of the formula Preparation of 1-(o-allyloxy-phenoxy)-2-hydroxy-3- [(a,a-dimethyl-n-propyl)-amino]-propane and its hydrochloride by Method A 12.3 gm (0.06 mol) of l-(o-allyloxy-phenoxy)-2,3- epoxy-propane were dissolved in 80 cc of ethanol, and 14 gm of 82% a,a-dimethyl-n-propyl-amine were added to the solution. The mixture was refluxed on a water bath for about three hours, and thereafter the reaction solution was evaporated to dryness in vacuo. The residue was dissolved in dilute hydrochloric acid, the solution was extracted with ether, the aqueous phase was made alkaline with sodium hydroxide, and the precipitated base was taken up in ether. The ethereal solution was dried, the ether was distilled off, and the residue, 14.8 gm of l-(o-allyloxy-phenoxy)-2- hydroxy-3-la,a-dimethyl-n-propyl)-amino]propane, was dissolved in acetonitrile. The resulting solution was acidified with ethereal hydrochloric acid, ether was added to the acid solution, and the precipitate formed thereby was recrystallized from acetone/ether, yielding 11.5 gm of the hydrochloride, m.p. 657()(., of the formula v on ('u" cin o cm o-crn r 'u -oirT-Nu- -(1J-CII;CII;-lltfl :3 on C111! EXAMPLE 3 Preparation of l-(o-hydroxymethyl-phenoxy)-2- hydroxy-3-[(a,a-dimethyl-n-propyl)-amino]-propane and its oxalate by Method A 6.2 gm (0.036 mol) of l-(o-hydroxymethylphenoxyl-Z,B-epoxy-propane were dissolved in 60 cc olcthanol, 4.5 gm (0.052 mol) of 82% a,a-dimethyl-n* propyl-amine were added to the solution, and the mixture was refluxed for 3 hours. Thereafter, the ethanol was distilled off, the residue was dissolved in dilute hydrochloric acid, the aqueous solution was extracted with ether, the acid aqueous phase was made alkaline with sodium hydroxide, and the precipitated base was taken up in ether. The ethereal phase was dried, the ether was distilled off, and the residue, 9.3 gm of l-(ohydroxymethyl-phenoxy)-2-hydroxy-3-[(a,a-dimethyln-propyl)-amino]-propane, was dissolved in acetone. The resulting solution was acidified with a solution of 3.8 gm of oxalic acid in acetone, ether was added thereto, and the crystalline precipitate formed thereby was recrystallized from acetone, yielding 4.9 gm of the oxalate, m.p. 146-l49C., of the formula [(a,a-dimethyl-npropyl)-aminol-propane and its hydrochloride by Method A A solution of 8.7 gm (0.l mol) of a,a-dimethyl-npropylamine in 25 cc of ethanol was added to a solution of 11.45 gm (0.05 mol) of l-(o-bromo-phenoxy)- 2,3-epoxypropane in 75 cc of ethanol. The mixed solution was refluxed for 2 hours and was then worked up as described in Example 3. The precipitated base was dissolved in ethanol, the solution was acidified with ethereal hydrochloric acid, and the precipitate formed thereby was recrystallized from ethanol/ether, yielding 8.0 gm of the hydrochloride, m.p. 1l9l22C., of the formula ether. The aqueous phase was evaporated to dryness in vacuo, and the residue was recrystallized twice from acetonitrile/ether, yielding 8.4 gm of the hydrochloride, m.p. l29-l3 1C., of the formula o it om Using a procedure analogous to that described in Example l, the following additional l-(o-cyanophenoxy)-2-hydroxy-3-alkylamino-propanes and their hydrochlorides of the formula were prepared from l-(o-cyano-phenoxy)-2.3epoxypropane and the corresponding primary amine of the formula III above:

lfii' R clllsii'di l i --CH2-( JCH3 -d)-C3H1 J-C4Ho 1O CH3 154-157 JC2H5 11 CH3 CH3 -148 CH2( J-CHa 12 -C(CzH5)a 157-158 (liC:i1I

14. Ulla 137-130 -(1 (lll2 l(l |l 15 (llIrr 218-220 (J-macho JC 1Irr J-(CH2)2iC:1I

( lHa EXAMPLE 19 Using a procedure analogous to that described in Example 1-(o-allyl-phenoxy)-2-hydroxy-3-[(04,0:- dimethyl-n-butyl)-amino]-propane hydrochloride, mp.

105- 106C, of the formula R1 propane and a,a-dimethyl-n-butyl-amine.

Using a procedure analogous to that described-in Example 5, the following additional l-(2'-chloro-5- hyd-roxy-3-alkyl-an1ino-propanes and the rides of the formula 7 8 EXAMPLE l8 Continued Using a procedure analogous to that described in Exp ample 2, l-(o-allyloxy-phenoxy)-2-hydroxy-3-[(a- Example R g I methyl-oz-ethyl-n-butyl)-amino]-propane hydrochlo- 5 ride, m.p. 89 92C, of the formula B Ha CHLZCIFCHFO 27 CH3 253-255 I ('Jtert- 01H, OCII2C|JIICH2NH 1 0 H3 I w 011 23 CH3 106-108 (CH )iC3H1 CH:3 H3

-0 CH CH2CH CH 2 152-1 CH2-CHz-CH3-HC1 -CCHZ))22-(OHZ)4(OH;) 102-132 um 31 C(CH;)zCHz-C(CH:); 174-176 was prepared from l-(o-allyloxy-phenoxy)-2,3-epoxy- Using a procedure analogous to that described in Expropane and a-methyl-a-ethyl-n-butyl-amine. 20 ample l, the following additional l-phenoxy-2- ir. hydrochlowere prepared from the corresponding l-phenoxy-2,3- propane and primary amine of the formula III:

methyl-phenoxy)-2-h ydroxy-3-alkylamino-propanes ggj' R fi fi gys g and therr hydrochlorrdes of the formula 32 CH3 13H -io31r7 II -()(Jll2-(lll( lIgNIIR-IICl 3 33 0m 4-0N 203-206 ()II at a -o-021r5 were synthesized from l-(2-chlor0-5-methyl-phenox- 012m y)-2,3-propane and the corresponding primary amine 5 34 124-126 of the formula 1]! above: )'C4lIn CH3 M.P. (hydrochloride), 35 C H3 4-C--0 C II; 144-146 Example No. R C. l

(/C4Il0 20 ,1 (1113 171-174 I i CH: o n

LUZ C 3 as om 3-N02 140-142 a i:om7 C I 1 -167 21 I I a 64 CH3 -(I)CZII5 22 nn 150-151 EXAMPLE 37 PC3117 By reduction of l-(3-nitro-phenoxy)-2-hydroxy-3- GHQ [(a,a-dimethyl-n-butyl)-amino]-propane (the free 23 (111; 132-134 base product of Example 36) with catalytically aCtl-w J; vated hydrogen, l-(3'-amino-phenoxy)-2-hydroxy-3- [(a,a-dimethyl-n-butyl)-amino]-propane was prepared, whose dlhydrochloride of the formula 24 CH3 152-154 NIIz 5H1 I (1H3 25 C(CzH )a 201-203 -o cm 1111- (:11, N1r-- --t:n,- cur-011121101 26 cm 189-1911 om 9 had a melting point of 173- 174C.

EXAMPLE 38 Preparation of 1-(o-cyano-phenoxy)-2-hydroxy-3 [(a,a-dimethyl n-pentyl)-amino]-propane and its hydrochloride by method A 2.1 gm (0.087 mol) of l-(o-cyano-phenoxy)-2- hydroxy 3-bromo-propane were dissolved in 50 cc of ethanol, 2 gm (0.0175 mol) of tert.heptylamine (a,a-dimethyl-n-pentylamine) were added to the solution, and the mixture was refluxed for two hours. Thereafter, the ethanol was distilled off, the residue was digested with dilute NaOH, the aqueous alkaline mixture was extracted with ether, the ethereal extract solution was washed with water and dried over magnesium sulfate, and the ether was distilled off. 3 gm of raw 1-(o-cyano-phenoxy)-2-hydroxy-3-[(a,a-dimethyl-npentyl)-amino]-propane remained behind, which were dissolved in a small amount of ethanol, the resulting solution was acidified with ethereal hydrochloric acid, and the precipitate formed thereby was recrystallized from ethanol/ether, yielding 2.8 gm of the hydrochloride, m.p. 144 145C, of the formula Preparation of l-(m-tolyloxy)-2-hydroxy-3-[(oz,adimethyl-n-pentyl)-amino]-propane and its hydrochloride by method B 500 mgm of |-(m-tolyloxy)-2-hydroxy-3-[(0z,adimethyl-n-penty)-amino]-propane tetrahydropyranyl ether were heated with cc of concentrated hydrochloric acid for two hours on a boiling water bath. Thereafter, the reaction mixture was allowed to cool, was then made alkaline with sodium hydroxide, and the precipitated raw base, l-(m-tolyloxy)-2-hydroxy-3- [(a,a-dimethyl-n-pentyl)-amino]-propane, was taken up in ether. The presence of the free aminoalcohol was confirmed by thin-layer chromatography of the ethereal solution. The solution was dried, evaporated, the residue was dissolved in a small amount of ethanol, and the solution was acidified with ethereal hydrochloric acid, whereby a small amount of the hydrochloride, m.p. 121 125C, of the formula (ills t) (111; 11 (111 Nll ((lllg)3Cll1]l(/l precipitated out.

The starting compound was prepared as follows: 4.6 gm (0.019 mol) of 1-(m-tolyloxy)-2-hydroxy-3-bromopropane were slowly admixed with 1.6 gm of dihydropyran in the presence of a catalytic amount of p-toluene-sulfonic acid, whereby an exothermic reaction occurred. After about 15 minutes the reaction mixture was dissolved in 50 cc of ethanol, 2.2 gm (0.019 mol) ofa,wdimethyl-n-pentyl-amine were added to the solution, and the mixture was refluxed for 5 hours. Thereafter, the ethanol was distilled off, the residue was dissolved in ether, and the solution was acidified with an ethereal oxalic acid solution. After some time of standing the oxalate of l(m-tolyloxy)-2-hydroxy-3-[(a,a-

10 dimethyl-n-pentyl)-amino]-propane tetrahydropyranyl ether, m.p. 118 122C, began to crystalize out. 1.2 gm of the compound were isolated.

EXAMPLE 40 Preparation of 1-(m'amino-phenoxyl-2-hydroxy3- [(a,a-dimethyl-n-butyl)-amino]-propane and its dihydrochloride by method C 7.1 gm (0.024 mol) of l-(m-nitro-phcnoxy)-2 hydroxy-3-[(ma-dimethyl-n-butyl)-amino]-propane were hydrogenated at 20C in 50 cc of methanol in the presence of Raney nickel. After absorption ofthe theo retical amount of hydrogen the catalyst was filtered off. the methanol was distilled out of the filtrate, and the residue, raw l-(m-amino-phenoxy)-2-hydroxy-3-[(a,adimethyl-n-butyl)-amino]-propane, was dissolved in ethanol. The ethanolic solution was acidified with ethereal hydrochloric acid, and the crystalline precipitate formed thereby was recrystallized by dissolving it in ethanol and adding ether to the solution. 1.5 gm of the dihydrochloride, m.p. 173 174C, of the formula in ether. The ethereal solution was washed with water,

dried over magnesium sulfate, and evaporated to dryness in vacuo. The solid residue was dissolved in ethyl acetate and recrystallized therefrom by addition of petroleum ether. The pure crystalline base, l-(o-cyano-pchloro-phenoxy)-2-hydroxy-3-[(a-methyl-a-ethyl-nbutyl)-amino]-propane, was dissolved in ether, and the resulting solution was acidified with ethereal hydrochloric acid. The precipitate formed thereby was collected and recrystallized from acetonitrile/ether, yielding 2 gm of the hydrochloride, m.p. 143 145C, of the formula [(a,a-dimethyl-n-butyl)-amino]-propane and its hydrochloride by method C 3.39 gm (0.01 mol) of l-(m-amino-phenoxy)-2- hydroxy-3-[(a,a-dimethy|-n-butyl)-aminol-propane hydrochloride were dissolved in 3.5 of concentrated hydrochloric acid, and the solution was diluted with 20 cc of water, The aqueous solution was cooled to C, and then, while stirring, a solution of 1.4 gm (0.02 mol) of NaNO in 10 cc of water was added dropwise over a period of 15 minutes. Thereafter, the mixture was stirred for 30 minutes more at 10C, and then a solution of 5 gm of CuSO, 5H O and 5.6 gm of potassium cyanide in 30 cc of water, heated to 90C, was added dropwise to the mixture at 8090C over a period of minutes, accompanied by stirring. Subsequently, the aqueous phase was decanted from resinous components which had formed and was then extracted with chloroform. The organic phase was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue, raw l-(m-cyano-phenoxy)-2-hydroxy-3- [(a,a'dimethyl-n-butyl)-amino]-propane, was dissolved in a small amount of ethanol, the solution was acidified with ethereal hydrochloric acid, and the crystalline precipitate formed thereby was recrystallized from ethanol/ether, yielding 0.7 gm of the hydrochloride, m.p. l38 140 C of the formula The compounds according to the present invention, that is, those embraced by formula 1 above and their nontoxic, pharmacologically acceptable acid addition salts, have useful pharmacodynamic properties. More particularly, they exhibit B-adrenolytic and hypotensivc activities in warm-blooded animals, as confirmed by in vivo tests on guinea pigs. Thus, the compounds of the invention are useful for the treatment and prophylaxis of diseases of the'coronary heart vessels and cardiac arrythmia, especially tachicardia, in warmblooded animals.

For pharmaceutical purposes the compounds accord ing to the present invention are administered to warmblooded animals perorally or parenterally as sole active ingredients or in combination with other pharmacodynamically active ingredients, such as coronary dilators or sympathicomimetics, in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. One effective dosage unit of the compounds according to the present invention is from 0.0166 to 5.0 mgm/kg body weight, preferably 0.083 to 1.67 mgm/kg (peroral) or 0.0166 to 0.34 mgm/kg (parenteral).

The following examples illustrate a few dosage unit compositions comprising a compound of the instant invention as an active ingredient and represent the best mode contemplated of putting the invention to practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 43 Tablets The tablet composition was compounded from the following ingredients:

Parts l-( o-Cyan o-phenoxy )-2-hyd roxy-S-l (01.0:- dimethyl-n-propyl )-amino ]-propane hydrochloride 40.0 Corn starch 164.0 Secondary calcium phosphate 240,0 Magnesium stearate l .0 Total 445.0

Compounding procedure:

The individual ingredients were intimately admixed with each other, the mixture was granulated in customary fashion, and the granulate was pressed into 445 mgm-tablets. Each tablet contained 40 mgm of the phenoxy-amino-propanol compound and, when administered perorally to a warm-blooded animal of about kg body weight in need of such treatment, produced very good B-adrenolytic effects.

EXAMPLE 44 Gelatin capsules The capsule filler composition was compounded from the following ingredients:

parts l-(o-Cyano-phenoxy)-2 hydroxy-3-[(a, adimethyl-n-butyl )-amino]-propane hydrochloride 25.0 Corn starch 175.0

Total 200.0

Compounding procedure:

The ingredients were intimately admixed with each other, and 200 mgm-portions ofthe mixture were filled into gelatin capsules of suitable size. Each capsule contained 25 mgm of the phenoxy-amino-propanol compound and, when administered perorally to a warmblooded animal of about 60 kg body weight in need of such treatment, produced very good B-adrenolytic effects.

EXAMPLE 45 Hypodermic solution The solution was compounded from the following ingredients:

propane hydrochloride 25 parts Sodium salt of EDTA 2 do. Distilled water q.s.ad 1000 do. by vol.

Compounding procedure:

The propanol compound and the EDTA salt were dissolved in a sufficient amount of distilled water, and the solution was diluted to the indicated volume with additional distilled water, filtered until free from suspended particles, and filled into l cc-ampules under aseptic conditions, which were finally sterilized and sealed. Each ampule contained 25 mgm of the phenoxy-amino-propanol compound, and when the contents thereof were administered intravenously to a warmblooded animal of about 60 kg body weight in need of such treatment, very good ,B-adrenolytic effects were produced.

EXAMPLE 46 Sustained release pills The pill core composition was compounded from the following ingredients:

' propanol Parts l-(o-Allyloxy-phenoxy)-2-hydroxy-3-[(a,a-

dimethyl-n-propyl)-amino]-propane hydrochloride 25.0 Carhoxymethyl cellulose (CMC) 295.0 Stearic acid 20.0 Cellulose acetate phthalate (CAP) 40.0 Total 380.0

Compounding procedure:

The propanol compound, the CMC and the stearic acid were intimately admixed with each other, the mixture was granulated in customary fashion with a solution of the CAP in 200 cc of a mixture of ethanol and ethyl acetate, and the granulate was pressed into 380 mgm-pill cores which were then coated with a sugarcontaining 5% solution of polyvinylpyrrolidone in water. Each pill contained 25 mgm of the phenoxy-aminopropanol compound and, when administered perorally to a warm-blooded animal of about 60 kg body weight in need of such treatment, produced very good ,B-adrenolytic effects.

EXAMPLE 47 Tablets with combination of active ingredients The tablet composition was compounded from the following ingredients:

Parts l-(o'Cyano-phenoxy J-Z-hydroxy-Il- [(ma-dimethyl-n-pro yl)-amino|]- propane hydrochlori e 35.0 2,6-Bis-(diethanolaniino)-4.X-dipiperidino-pyrimidol5,4-dl-pyrimidine 75.0 Lactose 164.0 Corn Starch 194.0 Colloidal silicic acid l4.0 Polyvinylpyrrolidone 6.0 Magnesium stearate 2.0 Soluble starch 10.0

Total 500.0

Compounding procedure:

The propanol compound, the lactose, the corn starch, the colloidal silicic acid and the polyvinylpyrrolidone were intimately admixed with each other, the mixture was granulated in customary fashion with an aqueous solution of the soluble starch, the granulate was admixed with the magnesium stearate, and the composition was pressed into 500 mgm-tablets. Each tablet contained 35 mgm of the phenoxy-aminocompound and 75 mgm of the pyrimidopyrimidine compound and, when administered perorally to a warmblooded animal of about 60 kg body weight in need of such treatment, produced very good B-adrenolytic and coronary dilating effects.

Analogous results were obtained when an equal amount of any one of the other compounds embraced by formula I above was substituted for the particular phenoxy-aminp-propanol compounds in Examples 43 through 47. Likewise, the amount of active ingredient in these examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit ofthe invention or the scope of the appended claims.

It. is claimed 1. A compound of the formula ceptable acid addition salt thereof.

Claims

1. A COMPOUND OF THE FORMULA

2. A compound according to claim 1, which is 1-(o-cyano-phenoxy)-2-hydroxy-3-(( Alpha Alpha -dimethyl-n-propyl)-amino)-propane or a non-toxic, pharmacologically acceptable acid addition sAlt thereof.

3. A compound according to claim 1, which is 1-(o-cyano-phenoxy)-2-hydroxy-3-(( Alpha Alpha -dimethyl-n-butyl)-amino)-propane or a non-toxic, pharmacologically acceptable acid addition salt thereof.